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[Display omitted] • The poorly water-soluble drug was successfully entrapped into SLNs for oral delivery. • In vitro release data was able to predict the rank order of the oral bioavailability. • The SLN formulations enhanced the bioavailability by 2.5 and 1.8 fold. • Lipid concentration and particle size had an impact on the bioavailability. • In vitro-in vivo correlation was achieved using numerical deconvolution. The present study investigated the oral bioavailability of celecoxib when incorporated into solid lipid nanoparticles either dissolved or suspended. In vitro drug release in different media, in vivo performance, and in vitro-in vivo correlation were conducted. The results revealed that the compound was successfully encapsulated into the nanocarriers with good physicochemical properties for oral administration. The in vitro release profiles followed the Weibull model, with significant differences between the formulations containing the solubilized and the suspended compound. Furthermore, in vitro release data could be used to rank the observed in vivo bioavailability. The relative bioavailability of celecoxib from the solid lipid nanoparticles was 2.5- and 1.8-fold higher for the drug solubilized and suspended solid lipid nanoparticle formulation, respectively, when compared to the celecoxib reference. A significant difference was observed between the plasma concentration–time profiles and pharmacokinetic parameters for the three investigated formulations. Finally, this investigation displayed promising outcomes that both solubilized and suspended celecoxib in the lipid core of the solid lipid nanoparticles offers the potential to improve the compound's oral bioavailability and thereby reduce the dosing frequency. [ABSTRACT FROM AUTHOR]

Formulation-induced microbiota changes were linked with pro-inflammatory response. [Display omitted] • Amorphous solid dispersion and lipid nanoemulsion improve lurasidone bioavailability. • Lipid nanoemulsion triggered reductions in gut microbiota diversity and abundance. • The PVP-based amorphous solid dispersion was 'gut neutral'. Increasing attention is being afforded to understanding the bidirectional relationship that exists between oral drugs and the gut microbiota. Often overlooked, however, is the impact that pharmaceutical excipients exert on the gut microbiota. Subsequently, in this study, we contrasted the pharmacokinetic performance and gut microbiota interactions between two commonly employed formulations for poorly soluble compounds, namely 1) an amorphous solid dispersion (ASD) stabilised by poly(vinyl pyrrolidone) K-30, and 2) a lipid nanoemulsion (LNE) comprised of medium chain glycerides and lecithin. The poorly soluble antipsychotic, lurasidone, was formulated with ASD and LNE due to its rate-limiting dissolution, poor oral bioavailability, and significant food effect. Both the ASD and LNE were shown to facilitate lurasidone supersaturation within in vitro dissolution studies simulating the gastrointestinal environment. This translated into profound improvements in oral pharmacokinetics in rats, with the ASD and LNE exerting comparable ∼ 2.5-fold improvements in lurasidone bioavailability, compared to the pure drug. The oral formulations imparted contrasting effects on the gut microbiota, with the LNE depleting the richness and abundance of the microbial ecosystem, as evidenced through reductions in alpha diversity (Chao1 index) and operational taxonomical units (OTUs). In contrast, the ASD exerted a 'gut neutral' effect, whereby a mild enrichment of alpha diversity and OTUs was observed. Importantly, this suggests that ASDs are effective solubility-enhancing formulations that can be used without comprising the integrity of the gut microbiota – an integral consideration in the treatment of mental health disorders, such as schizophrenia, due to the role of the gut microbiota in regulating mood and cognition. [ABSTRACT FROM AUTHOR]

[Display omitted] Developing co-amorphous systems is an attractive strategy to improve the dissolution rate of poorly water-soluble drugs. Various co-formers have been investigated. However, previous studies revealed that it is a challenge to develop satisfied acidic co-formers, e.g., acidic amino acids showed much poorer co-former properties than neutral and basic amino acids. Only a few acidic co-formers have been reported, such as aspartic acid, glutamic acid, and some other organic acids. Thus, this study aims to explore the possibility of adenosine monophosphate and adenosine diphosphate used as acidic co-formers. Mebendazole, celecoxib and tadalafil were used as the model drugs. The drug-co-former co-amorphous systems were prepared via ball milling and confirmed using XRPD. The dissolution study suggested that the solubility and dissolution rate of the drug-co-formers systems were increased significantly compared to the corresponding crystalline and amorphous drugs. The stability study revealed that using the two nucleotides as co-formers enhanced the physical stability of pure amorphous drugs. Molecular interactions were observed in MEB-co-former and TAD-co-former systems and positively affected the pharmaceutical performance of the investigated co-amorphous systems. In conclusion, the two nucleotides could be promising potential acidic co-formers for co-amorphous systems. [ABSTRACT FROM AUTHOR]

[Display omitted] Industrial-scale pharmaceutical applications still face many challenges in overcoming the low absorption and bioavailability of poorly water-soluble drugs. Hot-melt extrusion has emerged as a promising approach with continuous processing on an industrial scale for the preparation of drug delivery systems. Many reviews have mentioned the potential applications, processes, principles and advantages and disadvantages of hot-melt extrusion in the pharmaceutical industry. However, a focus on the recent progress of hot-melt extrusion, which investigates the impacts of processes and formulations of solid dispersions of poorly water-soluble drugs, is missing. In this review, various factors, including polymers, drug properties, additives and surfactants, in solid dispersion SD formulations by hot-melt extrusion will be discussed. Moreover, the effects of the hot-melt extrusion process on the physicochemical properties of solid dispersions will be mentioned. The utilization of molecular interactions in hot-melt extrusion to improve drug stability will also be described. Overall, this summary of recent studies on solid dispersion by hot-melt extrusion will provide perspectives and effectiveness for the development of formulations containing poorly water-soluble drugs. [ABSTRACT FROM AUTHOR]

Active pharmaceutical ingredient (API) nanosuspensions from naproxen (Nap) and itraconazole (Itra) stabilized with Kollidon®VA64 (KVA) and sodium dodecyl sulfate (SDS) were produced in two different size classes each by wet media milling. These API nanosuspensions were spray dried with lactose, trehalose and sucrose as matrix formers in different proportions and at different drying temperatures (T outlet). T outlet as well as the API content significantly influenced the redispersibility of the API nanoparticles. It could be shown that these two parameters are related to each other, with an increasing API content leading to a decreasing maximum applicable T outlet (T critical). Drying above T critical always led to an alteration of the size characteristics of the API nanoparticles and thus to a non-redispersible product with respect to the defined quality criteria. For each proportion of API to matrix former, a T critical could be found. T critical showed a linear relation to the API content. The linear regression of this relation was defined as process boundary. The y-intercept of the process boundary correlated well with the glass transition temperature (T g) of the pure matrix former used for spray drying. The two APIs under investigation led to virtually identical behaviour if other parameters were kept constant. The particle size of the initial nanosuspension had an important influence. Nanosuspensions with comparatively small particle sizes led to a significantly stronger decrease of the process boundaries compared to the use of larger particle sizes. The maximum API content that leads to a redispersible product is thus decisively determined by Toulet of the spray dryer, T g as well as the proportion of the matrix former and by the particle size of the API nanoparticles used. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Hot-melt extrusion allows for the continuous production of amorphous solid dispersions, which are used to enhance bioavailability of poorly soluble drugs in pharmaceutical drug delivery. To facilitate formulation and extrusion process development, we propose a mathematical model describing the formation of amorphous solid dispersions in the context of this process. The model is based on the calculation of two key process values: (1) time to dissolution of solid drug particles in molten polymer during extrusion and (2) mean residence of material in the extruder. We suggest that their linking allows for rational process design. Experimental data support the validity of our model for both key process values as well as the overall process. This modeling approach allows for fast and cost-effective formulation and extrusion process development as well as feasibility estimations in early stages of drug development. [ABSTRACT FROM AUTHOR]

Lipid based-formulations can enhance the bioavailability of poorly water-soluble lipophilic drugs through enhanced solubilisation of drugs in the gastrointestinal (GI) tract during digestion. This study investigates the solubilisation behaviour of poorly water-soluble drugs upon digestion of solid self-microemulsifying drug delivery system (S-SMEDDS). The S-SMEDDS were prepared using two different core lipids, Gelucire® 44/14 (GEL) or glyceryl monooleate (GMO), and were loaded with two model drugs, fenofibrate (FEN) and cinnarizine (CINN). S-SMEDDS formulations were characterized using wide-angle X-ray scattering (WAXS) and Raman spectroscopy, and their structural behaviour and drug solubilisation behaviour were monitored using drug-related diffraction peaks during digestion under fasted and fed simulated intestinal conditions using time-resolved small and wide-angle X-ray scattering (SAXS/WAXS). The concentrations of FEN and CINN released into the aqueous phase (AP) during digestion were quantified using high-performance liquid chromatography (HPLC). Both model drugs, FEN and CINN, had greater solubility in the GMO-based S-SMEDDS formulations and were partially solubilised into lipid matrix and uniformly distributed in solid formulations. The extent of digestion was greater for the GEL-based systems (92–94%) than GMO-based systems (65–75%) as was the rate of digestion. GEL-based S-SMEDDS formulations formed a lamellar phase during digestion in the fasted state and formed mixed micelles in the fed state. In contrast, the GMO-based system formed the mixed micelles in both intestinal conditions. The time-resolved SAXS profiles revealed solubilisation of crystalline drugs into the lipolysis products. Synchrotron SAXS results were in correlation with the HPLC measurements, confirming the ability of the SAXS technique to monitor drug behaviour and showing that the digestion of S-SMEDDS can enhance drug solubilisation. [ABSTRACT FROM AUTHOR]

Ziprasidone is a poorly water-soluble antipsychotic drug that demonstrates low fasted state oral bioavailability and a clinically significant two-fold increase in absorption when dosed postprandially. Owing to significant compliance challenges faced by schizophrenic patients, a novel oral formulation of ziprasidone that demonstrates improved fasted state absorption and a reduced food effect is of major interest, and is therefore the aim of this research. Three lipid-based drug delivery systems (LBDDS) were developed and investigated: (a) a self-nanoemulsifying drug delivery system (SNEDDS), (b) a solid SNEDDS formulation, and (c) silica–lipid hybrid (SLH) microparticles. SNEDDS was developed using Capmul MCM® and Tween 80®, and solid SNEDDS was fabricated by spray-drying SNEDDS with Aerosil 380® silica nanoparticles as the solid carrier. SLH microparticles were prepared in a similar manner to solid SNEDDS using a precursor lipid emulsion composed of Capmul MCM® and soybean lecithin. The performance of the developed formulations was evaluated under simulated digesting conditions using an in vitro lipolysis model, and pure (unformulated) ziprasidone was used as a control. While pure ziprasidone exhibited the lowest rate and extent of drug solubilization under fasting conditions and a significant 2.4-fold increase in drug solubilization under fed conditions, all three LBDDS significantly enhanced the extent of drug solubilization under fasting conditions between 18- and 43-folds in comparison to pure drug. No significant difference in drug solubilization for the fed and fasted states was observed for the three LBDDS systems. To highlight the potential of LBDDS, mechanism(s) of action and various performance characteristics are discussed. Importantly, LBDDS are identified as an appropriate formulation strategy to explore further for the improved oral delivery of ziprasidone. [ABSTRACT FROM AUTHOR]

Triglycerides (TG) are one of the most common excipients used in oral lipid-based formulations. The chain length of the TG plays an important role in the oral bioavailability of the co-administered drug. Fatty acid (FA) chain-length specificity of porcine pancreatic lipase was studied by means of an in vitro lipolysis model under bio-relevant conditions at pH 6.80. In order to determine the total extent of lipolysis, back-titration experiments at pH 11.50 were performed. Results suggest that there is a specific chain length range (C2–C8) for which pancreatic lipase shows higher activity. This specificity could result from a combination of physicochemical properties of TGs, 2-monoglycerides (2-MGs) and FAs, namely the droplet size of the TGs, the solubility of 2-MGs within mixed micelles, and the relative stability of the FAs as leaving groups in the hydrolysis reaction. During experimentation, it was evident that an optimisation of lipolysis conditions was needed for tighter control over pH levels so as to better mimic in vivo conditions. 1 M NaOH, 3.5 mL/min maximum dosing rate, and 3 μL/min minimum dosing rate were the optimised set of conditions that allowed better pH control, as well as the differentiation of the lipolysis of different lipid loads. [ABSTRACT FROM AUTHOR]

Drug loading into porous carriers may improve drug release of poorly water-soluble drugs. However, the widely used impregnation method based on adsorption lacks reproducibility and efficiency for certain compounds. The aim of this study was to evaluate a drug-loading method based on solvent evaporation and crystallization, and to investigate the underlying drug-loading mechanisms. Functionalized calcium carbonate (FCC) microparticles and four drugs with different solubility and permeability properties were selected as model substances to investigate drug loading. Ibuprofen, nifedipine, losartan potassium, and metronidazole benzoate were dissolved in acetone or methanol. After dispersion of FCC, the solvent was removed under reduced pressure. For each model drug, a series of drug loads were produced ranging from 25% to 50% (w/w) in steps of 5% (w/w). Loading efficiency was qualitatively analyzed by scanning electron microscopy (SEM) using the presence of agglomerates and drug crystals as indicators of poor loading efficiency. The particles were further characterized by mercury porosimetry, specific surface area measurements, differential scanning calorimetry, and USP 2 dissolution. Drug concentration was determined by HPLC. FCC-drug mixtures containing equivalent drug fractions but without specific loading strategy served as reference samples. SEM analysis revealed high efficiency of pore filling up to a drug load of 40% (w/w). Above this, agglomerates and separate crystals were significantly increased, indicating that the maximum capacity of drug loading was reached. Intraparticle porosity and specific surface area were decreased after drug loading because of pore filling and crystallization on the pore surface. HPLC quantification of drugs taken up by FCC showed only minor drug loss. Dissolution rate of FCC loaded with metronidazole benzoate and nifedipine was faster than the corresponding FCC-drug mixtures, mainly due to surface enlargement, because only small fractions of amorphous drug (12.5%, w/w, and 8.9%, w/w, respectively) were found by thermal analysis. Combination of qualitative SEM analysis and HPLC quantification was sufficient to proof the feasibility of the solvent-evaporation method for the loading of various drugs into FCC. Mechanistic investigation revealed that a high specific surface area of the carrier is required to facilitate heterogeneous nucleation, and large pore sizes (up to 1 μm) are beneficial to reduce crystallization pressures and allow drug deposition within the pores. The solvent-evaporation method allows precise drug loading and appears to be suitable for scale-up. [ABSTRACT FROM AUTHOR]

In this study, febantel was dissolved under increased temperature in a nonionic surfactant Lutrol L44® and subsequently mixed into an aqueous maltodextrin solution. After 8h under static conditions, coacervation or phase separation took place. 1H NMR spectra and HPLC analysis showed that the upper phase contained mainly all febantel, while no febantel was detected in the lower phase. Fluorescent microscopy showed that maltodextrin is distributed in the lower phase. Coacervation proved to be a promising formulation technology for certain poorly water-soluble drugs, such as febantel. The coacervate phase showed an increase in in vitro dissolution kinetics, compared to Rintal® granules. These results were confirmed in an in vivo study performed on dogs. Febantel and fenbendazole showed a significant increase in plasma concentration compared to Rintal® granules. Further studies have to be performed to transform coacervates into a solid dosage form and to prove broad applicability to other poorly soluble drugs. [ABSTRACT FROM AUTHOR]

Abstract: pH-sensitive polymeric nanoparticles are promising for oral drug delivery, especially for peptide/protein drugs and poorly water-soluble medicines. This review describes current status of pH-sensitive polymeric nanoparticles for oral drug delivery and introduces the mechanisms of drug release from them as well as possible reasons for absorption improvement, with emphasis on our contribution to this field. pH-sensitive polymeric nanoparticles are prepared mainly with polyanions, polycations, their mixtures or cross-linked polymers. The mechanisms of drug release are the result of carriers’ dissolution, swelling or both of them at specific pH. The possible reasons for improvement of oral bioavailability include the following: improve drug stability, enhance mucoadhesion, prolong resident time in GI tract, ameliorate intestinal permeability and increase saturation solubility and dissolution rate for poorly water-soluble drugs. As for the advantages of pH-sensitive nanoparticles over conventional nanoparticles, we conclude that (1) most carriers used are enteric-coating materials and their safety has been approved. (2) The rapid dissolution or swelling of carriers at specific pH results in quick drug release and high drug concentration gradient, which is helpful for absorption. (3) At the specific pH carriers dissolve or swell, and the bioadhesion of carriers to mucosa becomes high because nanoparticles turn from solid to gel, which can facilitate drug absorption. [Copyright &y& Elsevier]

Abstract: The bioavailability of the poorly soluble model drug halofantrine, dosed in a soy bean oil solution or in a self-nanoemulsifying drug delivery system (SNEDDS), at two levels of lipid, was assessed in rats. Three rat models were used: intact rats, sham-operated rats and bile duct cannulated rats. The study showed no difference in the pharmacokinetic parameters between intact and sham-operated rats. T max increased with lipid load for both oil solution and SNEDDS, whereas C max and the absolute bioavailability were significantly higher for the SNEDDS at both lipid dosing levels. Bile duct cannulation of the rats reduced the C max and the absolute bioavailability of halofantrine significantly, by a factor of 2, for all 4 treatments. These data clearly demonstrate that bile has an importance for the absorption of drugs from lipid-based formulations independent of the type. [Copyright &y& Elsevier]

Abstract: The purpose of this research was to investigate the influence of dry coating micronized cohesive powders of a poorly water-soluble drug, indomethacin with force control agents, on its dissolution performance. A dry mechanical fusion method (mechanofusion) was used to coat indomethacin powders with magnesium stearate (0.25%,1%,5%) and sodium stearate (5%). After mechanofusion, significantly increased bulk and tapped densities and decreased intrinsic cohesion were observed for all samples. X-ray photoelectron spectroscopy analysis confirmed that a thicker magnesium stearate surface coating was achieved with increasing concentrations of the material. Dissolution was studied using the USP paddle method in buffer pH 5.0; several modelling approaches were used to explore the dissolution mechanisms. Whilst the bi-exponential equation represented dissolution of mechanofused indomethacin powders occurring from dispersed and agglomerated particles, it provided unrealistic parameter estimates for the two coating materials of contrasting properties. Initial increases in indomethacin dissolution were dependent on the concentration of magnesium stearate mechanofused onto the drug powders. The dissolution enhancing effect of indomethacin powders mechanofused with 5% sodium stearate was attributed to its surfactant properties that increased dispersion of indomethacin agglomerates. Initial drug release from the coated powders was described by a matrix-diffusion system according to the Higuchi model. [Copyright &y& Elsevier]

Abstract: The objective of this work was to investigate the influence of various micronized poorly water-soluble inorganic materials on the dissolution and de-agglomeration behaviour of a micronized, poorly water-soluble model drug, indomethacin, from lactose interactive mixtures. Dissolution of indomethacin was studied using the USP paddle method and the data were modelled with multi-exponential equations using a nonlinear least squares algorithm in order to obtain key parameter estimates. The dispersion of indomethacin mixtures was measured by laser diffraction. The addition of aluminium hydroxide and calcium phosphate to binary mixtures of indomethacin counter-intuitively improved the dissolution rate of indomethacin due to significant increases in both the estimated initial concentration and dissolution rate constant of dispersed particles of indomethacin. While some enhancement was due to pH changes in the dissolution medium, the presence of these poorly water-soluble inorganic salts caused de-agglomeration. Average particle size distributions indicated that the presence of aluminium hydroxide within the matrix of indomethacin had reduced the agglomerate concentration whilst increasing the dispersed particle concentration. These findings provide the first evidence of the ability of poorly water-soluble inorganic salts to enhance the de-agglomeration and dissolution of micronized powders, potentially translating to improved bioavailability of poorly water-soluble drugs. [Copyright &y& Elsevier]

Abstract: The main objective of this study was to prepare a solid form of lipid-based self-emulsifying drug delivery system (SEDDS) by spray drying liquid SEDDS with an inert solid carrier Aerosil 200 to improve the oral bioavailability of poorly water-soluble drug dexibuprofen. The liquid SEDDS was a system that consisted of dexibuprofen, Labrasol, Capryol 90 and Labrafil M 1944 CS. The particle size analysis revealed no difference in the z-average particle diameter of the reconstituted emulsion between liquid and solid SEDDS. The solid SEDDS was characterized by SEM, DSC and XRD studies. In vivo results of solid SEDDS and dexibuprofen powder in rats at the dose of 10mg/kg showed that the initial plasma concentrations of drug in solid SEDDS were significantly higher than those of dexibuprofen powder (P <0.05). The solid SEDDS gave significantly higher AUC and Cmax than did dexibuprofen powder (P <0.05). In particular, the AUC of solid SEDDS was about twofold higher than that of dexibuprofen powder. Our results suggested that this solid SEDDS could be used as an effective oral solid dosage form to improve the bioavailability of poorly water-soluble drug dexibuprofen. [Copyright &y& Elsevier]

Abstract: This study determined the influence of mixing speed and time on the dissolution and deagglomeration of a micronised, poorly water-soluble drug, indomethacin, in lactose interactive mixtures. Mixing occurred in a Turbula mixer; dissolution studies were performed using the USP paddle method, and the extent of deagglomeration was determined using modelling strategies and laser diffraction particle sizing of the powder mixtures. During low energy mixing at low rates and short mixing times, dissolution profiles showed an unusual flat asymptote indicating incomplete extents of dissolution caused by agglomerates that did not readily disperse in the dissolution medium. The study showed that increasing both speed and time of mixing increased the extent of dissolution and deagglomeration of the indomethacin powder. Nonlinear least squares modelling of the dissolution data using a sigmoidal equation provided estimates of the extent and rate of dissolution. Mixing speed and time had a much greater influence on the extent of dissolution which was controlled by deagglomeration than on the initial dissolution rate which was related to dispersed indomethacin. While some deagglomeration did occur at higher mixing energies, the deagglomeration of the indomethacin was not complete with only about 58–80% of indomethacin particles overlapping with the primary indomethacin particle size distribution. The significant outcome of this study was that mixing conditions have a major influence on the mixing quality, especially in areas where agglomerate characteristics influence performance. [Copyright &y& Elsevier]

Abstract: The objective of the study was to investigate the effect of fine lactose on the in vitro dissolution of indomethacin in interactive mixtures containing spray-dried lactose and lactose monohydrate (106–250μm). Dissolution of the indomethacin was measured using an automated dissolution apparatus following the USP paddle method at 100rpm. The particle size distributions of indomethacin mixtures were measured using a Mastersizer S under non-sink conditions. Data fitted bi-exponential or tri-exponential dissolution models, representing dissolution from dispersed and agglomerated particle distributions. The addition of fine lactose (VMD 3.8±0.4μm) to 20% indomethacin-coarse lactose mixtures resulted in significantly increased rates of dissolution caused by increases in the estimated dissolution rate constants for dispersed particles (K d) and by de-agglomeration. Agglomerates in the mixture showed little tendency to comminute under shear pressure. De-agglomeration in the dissolution medium was attributed to increased porosity of agglomerates, caused by dissolution of water soluble fine lactose in the agglomerate structure. The median particle size (D 50) of the dispersed particle distribution decreased with increasing concentrations of added fine lactose, indicating increasing extents of de-agglomeration, and a good correlation between K d and (D 50)2 resulted for the coarse lactose-based mixtures (R 2 >0.984). [Copyright &y& Elsevier]

This paper describes a means to predict the absorbability of poorly water-soluble drugs in humans based on rat intestinal permeability assessed by the in vitro Ussing-type chamber method. We investigated the correlation between the apparent permeability coefficients (Papp) of 10 water-soluble drugs obtained by the in vitro chamber method, in which the excised rat small intestinal tissue was used as the membrane, and the fractions absorbed (Fa) in humans. Using this correlation, we predicted Fa values of 5 poorly water-soluble drugs based on their Papp obtained through our modified chamber method using an additive. For water-soluble drugs, a good correlation between Papp and Fa, expressed by the equation: Fa=1-exp(-Papp×1.51×105)(r2=0.920), was found. The poorly water-soluble drugs used in the present study could be solubilized with 5% (final concentration) dimethylsulfoxide, and their Papp could be obtained through our modified chamber method. For poorly water-soluble drugs whose dose:solubility ratio ranged from 2500 to 3500 ml, predicted Fa values were favorably comparable with their Fa values reported in humans in the literature. These results showed that the in vitro Ussing-type chamber method was a useful method for predicting the Fa of poorly water-soluble drugs. [Copyright &y& Elsevier]